1. Field of the Invention
The invention relates to a transdermal therapeutic system (TTS) for controlled release of oestradiol in combination with norethisterone acetate to the human skin.
2. Description of the Prior Art
Oestradiol in combination with norethisterone acetate has a very low saturation solubility in the auxiliaries normally used to formulate transdermal therapeutic systems, such as polyacrylate adhesives, tackifiers, plasticizers and absorption improvers. As a result, the capacity to load a TTS with dissolved active ingredient is greatly limited, and/or, in the case of supersaturation, unwanted crystallization occurs during storage. Consequently, the proportion of dissolved active ingredients in the matrix is reduced, which has an adverse effect on their release.
For combined preparations comprising oestradiol and norethisterone acetate, administration forms have been developed in which the active ingredients in a transdermal therapeutic system are contained in separate areas. However, manufacturing such TTSs is very expensive.
Accommodating drying agents together with transdermal therapeutic systems in the primary packaging reduces the risk of recrystallization but is far from straightforward.
DE-A 43 36 557 describes an active substance transdermal therapeutic system based on a pressure-sensitive adhesive which comprises rosin esters. It is prepared by kneading the components in the melt at temperatures between 100 and 140° C. and then carrying out coating. Such high temperatures in the preparation of pharmaceutical forms carry with them the risk that degradation products may be formed in an unacceptably high amount.
WO 95/30409 describes a topical polymer release system for the administration of certain active ingredients by means of a propellantless aerosol pump. The absence of adhesives is emphasized as an advantage. Additional components used include crystallization inhibitors/stabilizers and/or penetration enhancers such as substituted cyclodextrins, Transcutol, urea and isoterpenes; the active substance combination of oestradiol and norethisterone acetate is not claimed.